This proposal represents a continuing highly integrated examination of the mechanism by which injured tissue elicits a response from the host and the harmful effects of this response. Data derived from our past studies of the antibody-complement-mast cell pro-inflammatory response system suggests that, in model reperfusion injuries and model burns, this linked system causes more tissue loss than the original insult itself. Accordingly, interference with antibody-binding or complement activation or mast cell activation has produced a diminution in the extent of final injury. Thus, we hypothesize that major injury is critically exacerbated by the autologous inflammatory response. We wish to understand, in detail, (1) the exact sequence from injury antigen expression to necrosis;(2) whether natural IgM is a critical component;(3) how murine injury might parallel events in human;and (4) how to synthesize these findings into an effective therapeutic strategy to reduce the adverse effects of human injury. The Trauma Center Core (Project 1) will provide administrative support for these projects as well as provide financial support for consistent animal experiments and development of novel murine stains. Project 2 and 4 propose to study common mechanisms shared by mice and humans. Project 3 seeks to discover the exact mechanism of mast cell activation and mast cell-dependent tissue loss. By this funding mechanism, we wish to efficiently, and by multiple techniques, arrive at specific therapy for reperfusion injury and thermal burns. Successful therapy both lessens the ensuing disability from the local wound and may lessen the systemic impact by reductions in shock and secondary injury in response to systemic inflammation.